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Psychopathology and Cognition As Markers of Risk for Bipolar Disorder Psychopathology and cognition as markers of risk for bipolar disorder Sumit Mistry Thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy 20 20 Acknowledgements Having entered this PhD with a limited understanding of Psychiatry and Genetics, the completion of this thesis would not have been possible without support from a number of individuals. I am extremely grateful to my PhD supervisors Professors Stanley Zammi t, Daniel Smith and Valentina Escott - Price for their continuous support throughout my PhD. I am truly appreciative of their time and energy, keeping me on track, discu ssing ideas and results with me even though they are so busy . Stan has been nothing short of an excellent supervisor. His understanding of me having bipolar disorder and the difficulties that are associated with having the disorder have truly enabled me to get through the PhD process and to submit this thesis. Both Stan and Danny have read man y iterations of my drafts for publication s and helped me with addressing reviewer comments, something I had not do ne before. I would like to thank my co -authors Dr Hannah Jones from the University of Bristol , and Dr s Judith Harrison and Ar ianna Di Florio from Cardiff University for their help with running C onfirmatory Factor A nalysis ( Chapter 4 ), checking full texts for the systematic review (C hapter 6) and being the Cardiff University PGC Bipolar Disorder lead respectively. I would also like to thank them for reading the final manuscripts which have been adapted for use in this thesis in C hap ters 4, 6, 7 and 8 . Further, I am appreciative to all the families and children who took part in the ALSPAC study, givin g their time, data and biological samples, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionis ts and nurses. I am truly grateful to my funders Mental Health Research UK for their funding in al lowing me to complete this PhD, the NIHR Bristol BRC, the UK Medical Research Council and Wellcome Trust. Thanks must be g iven to the Psychiatric Genomics Consortium Bipolar Group for providing the genetic data to us e as a iii discovery dataset summary statistics for deriving my bipolar disorder polygenic risk score . I am greatly humbled by my colleagues and friends for helping me through the tough times, alw ays providing me with support, both morally and practically. I would personally like to thank Dr Judith Allardyce for being such a friendly face and friend from the start of my PhD. She has often discussed her work and my own work and how I could progress forward with ideas. I think we managed to keep each other sane! I am forever grateful to my parents Vinod and Sangeeta Mistry , and my sister and brother -in -law Naomi and Joe Leverton for being there through the many ups and downs throughout my life and throughout the PhD process. It has been a very long road to get to this point: First I was diagnosed with Chronic Fatigue Syndrome at 16 and then perhaps the most life changing experience for all of us when I stopped breathing multiple times while in hospital on my 21 st birthday . I woke up with no recollection of who I was, who my family were and who people are/the places I have been. I woke paralysed from the waist down , could not write and ha d a stutter . Years later I was sectioned and then at 26 years old , was diagnosed with bipolar disorder. When I did not know who I was or who you were, you stood by me and no matter what I know , I have you in my life and in my heart. It is therefore to them tha t I dedicate this thesis and to say, “We did it! ” iv Thesis Summary Bipolar disorder (BD) is a fairly common, highly heritable psychiatric disorder which can be highly disabling to those who suffer from it. There is a limited understanding of early precursors to BD that might be helpful to inform prediction models and knowledge of aetiology. Few population -based longitudinal studies have examined associations between measures of childhood psychopathology/cognitive funct ioning and BD, or phenotypic manifestations of increased genetic risk for BD in childhood. I investigated whether childhood psychopathology and cognitive domains examined from ages 8 -11 years were associated with hypomania examined at ages 22 -23 years. I then conducted a systematic review to identify phenotypes associated with genetic risk for BD, measured using a polygenic risk score (PRS) approach. Finally, I investigated whether increased genetic risk for BD, using a BD -PRS, was associated with various psychopathology and cognitive domains in childhood and hypomania in young adulthood. Findings from Chapter 4 suggest that borderline personality disorder (BPD) traits in childhood are strongly associated with hypomania, particularly the ‘risk - taking/irri table’ factor. Better performance in the domains of working memory, problem solving ability, verbal learning and emotion recognition are also associated with hypomania, with stronger association with the ‘active/elated’ factor (Chapter 5). Findings from Ch apter 6 highlight a limited literature on phenotypic manifestations of increased genetic risk for BD in childhood/adolescence. Individuals with increased genetic risk for BD are more likely to have ADHD, and have poorer executive functioning, processing sp eed and performance IQ in childhood (Chapters 7 and 8). This thesis adds to a limited literature examining associations between measures of childhood psychopathology/cognition and hypomania in the general population, and about how increased genetic risk for BD is manifest in childhood/adolescence. Further work to examine the robustness of these v findings in other populations at various stages of development are required, and to elucidate the mechanisms that underlie the associations observed. vi Publications resulting from work in this thesis Mistry, S., Zammit, S., Escott -Price, V., Jones, H., Smith, D.J. (2017). Borderline Personality and Attention -Deficit Hyperactivity traits in childhood are associated with hypomanic feature in early adulthood. Journal of Affective Disorders , 221 , 246 -253 https://doi.org/10.1016/j.jad.2017.06.039 Mistry, S., Harrison, J.R., Smith, D.J., Escott -Price, V., Zammit, S. (2017). The use of polygenic risk scores to identify phenotypes associated with genetic risk of schizophrenia : S ystematic review. Schizophrenia Research , 197 , 2-8 https://doi.org/10.1016/j.schres.2017.10.037 Mistry, S., Harrison, J.R., Smith, D.J., Escott -Price, V., Zammit, S. (201 8). The use of polygenic risk scores to identify phenotypes associated with genetic risk of bipola r disorder and depression : A s ystematic Review. Journal of Affective Disorders , 234 , 148 -155 https://doi.org/10.1016/j.jad.2018.02.005 Mistry, S., Escott -Price, V., Florio, A.D., Smith, D.J. , and Zammit, S. (201 9). Genetic risk for bipolar d isorder and psychopathology from childhood to early adulthood. Journal of Affective Disorders , 246 , 633 -639 Mistry, S., Escott -Price, V., Smith, D.J., Zammit, S. (201 9). Investigating associations between genetic risk for bipolar disorder and cognitive functioning in childhood . Journal of Affective Disorders , 259 , 112 -120 Mistry, S., Escott -Price, V., Smith, D.J., Zammit, S. (2020). Investigating associations between cognitive functioning in childhood and hypomania in young adulthood. Article due for submission to Journal of Affective Disorders vii Additional, related publicati ons to which I have contributed Richards, A., Horwood, J. O’Donnovan, M., Boden,J., Sellers, R., Riglin, L., Mistry, S., Kennedy, M., Harold, G. (201 9). Associations between schizophrenia genetic risk, anxiety disorders and manic/hypomanic episode in a longitudinal adult population cohort. British Journal of Psychiatry 214 , 96 -102 Harrison, J.R., Mistry, S., Muskett, N., E scott -Price, V. (2020) . From polygenic scores to precision medicine in Alzheimer’s Disease: A systematic review . Journal of Alzheimer’s Disease (Article in press) viii Table of Contents Psychopathology and cognition as markers of risk for bipolar disorder ..... i Declaration and Statements ................................ ................................ .................... i Acknowledgements ................................ ................................ ................................ iii Thesis Summary ................................ ................................ ................................ ...... v Publications resulting from work in this thesis ................................ ............... vii Additional, related publications to which I have contributed ...................... viii Index of Tables ................................ ................................ ................................ ....... xv Index of Figures ................................ ................................ ................................ ..... xvii Index of Appendices ................................ ................................ ............................ xviii Chapter 1: General Introduction ................................ ................................ ........... 1 1.1 A short history of BD ................................ ................................ ............................... 1 1.2 Classification of BD ................................ ................................ ................................ .. 2 1.2.1 Issues with the current classification
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